Abstract
Iron scavenging constitutes a crucial challenge for survival of pathogenic microorganisms in the iron-poor host environment. Candida albicans, like many microbial pathogens, is able to utilize iron from hemoglobin, the largest iron pool in the host's body. Rbt5 is an extracellular glycosylphosphatidylinositol (GPI)-anchored heme-binding protein of the CFEM family that facilitates heme-iron uptake by an unknown mechanism. Here, we characterize an additional C. albicans CFEM protein gene, PGA7, deletion of which elicits a more severe heme-iron utilization phenotype than deletion of RBT5. The virulence of the pga7−/− mutant is reduced in a mouse model of systemic infection, consistent with a requirement for heme-iron utilization for C. albicans pathogenicity. The Pga7 and Rbt5 proteins exhibit distinct cell wall attachment, and discrete localization within the cell envelope, with Rbt5 being more exposed than Pga7. Both proteins are shown here to efficiently extract heme from hemoglobin. Surprisingly, while Pga7 has a higher affinity for heme in vitro, we find that heme transfer can occur bi-directionally between Pga7 and Rbt5, supporting a model in which they cooperate in a heme-acquisition relay. Together, our data delineate the roles of Pga7 and Rbt5 in a cell surface protein network that transfers heme from extracellular hemoglobin to the endocytic pathway, and provide a paradigm for how receptors embedded in the cell wall matrix can mediate nutrient uptake across the fungal cell envelope.
Highlights
Candida albicans, a commensal fungus normally residing on the skin and on mucosal surfaces, is commonly able to cause local mucosal, cutaneous and nail infections
Pga7 is essential for heme-iron utilization Of the two extracellular C. albicans proteins, Rbt5 and Rbt51, that were previously shown to bind hemin, only the rbt52/2 mutant was defective in heme-iron utilization, and this defect was only partial, since an increase in hemoglobin concentration could restore growth [14]
Even in individual growing cells, porosity is probably not uniform, and it is likely that mature cell wall is less porous than the newly synthesized cell wall at the bud or hyphal tip of growing cells, and may require a system for transporting even relatively small molecules
Summary
A commensal fungus normally residing on the skin and on mucosal surfaces, is commonly able to cause local mucosal, cutaneous and nail infections. A siderophoremediated iron uptake mechanism requires the hydroxamate type siderophore transporter Sit1/Arn1 [10,11]. The heme iron acquisition pathway relies on Rbt, an extracellular GPI-anchored heme receptor [14]. A mutant of the vacuolar ATPase is defective only in heme-iron utilization, but not in endocytosis [18]. Together, these genetic studies suggested a pathway of heme-iron utilization in which interaction of free heme or hemoglobin with an extracellular receptor such as Rbt eventually leads to endocytosis, degradation of the protoporphyrin rings by heme oxygenase, and uptake of the released iron into the cytoplasm by a vacuolar iron permease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
